Substantial evidence has demonstrated a role for the Notch gene family in multiple human cancers, including neoplasms of the lymphoid system, pancreas, breast and CMS, among others. However, the pathophysiological mechanism of Notch function remains poorly understood. The underlying hypothesis of this proposal is that deregulation of the Notch signal transduction pathway drives the neoplastic conversion of cells, playing an important role in both the initiation and maintenance of the transformed state. This transforming activity is an intrinsic property of Notch and Notch mediates its effects through a signaling complex(s). My laboratory has developed in vitro strategies to study the mechanism of action of the mammalian Notch signal transduction pathway in the neoplastic transformation of cells. Research proposed herein is designed to seek a better understanding of the molecular nature of Notch and how activation of Notch subverts the normal physiology of the cell and deregulates growth controls. Specific aims for this proposal include; structure and function analysis of Notch, characterization of the Notch signaling complex, mechanism of cell cycle regulation and regulation of gene expression by Notch. The long-range goal for these studies is to obtain a comprehensive understanding of how Notch activity transforms cells in order to contribute to the rational design of cancer therapeutics. [unreadable] [unreadable] [unreadable]